Gitter B D, Cox L M, Carlson C D, May P C
Neuroscience Diseases Research Division, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Neuroimmunomodulation. 2000;7(3):147-52. doi: 10.1159/000026432.
Chronic neurodegeneration in the brains of Alzheimer's disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Abeta) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Abeta-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1beta (IL-1beta)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10-25 microM peptide. In addition, human amylin markedly potentiated IL-1beta-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1beta. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Abeta, extracellular Ca(2+) was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar beta-sheeted secondary-structure- and extracellular-Ca(2+)-dependent mechanisms.
阿尔茨海默病（AD）患者大脑中的慢性神经退行性变可能至少部分是由β-淀粉样蛋白（Aβ）以构象依赖的方式加剧炎症途径所介导的。在这方面，我们之前报道过，Aβ肽介导的白细胞介素-1β（IL-1β）刺激的人星形细胞瘤细胞炎性细胞因子分泌增强是构象依赖的。其他具有淀粉样变性的肽，如人胰岛淀粉样多肽，也表现出类似的构象依赖性神经毒性作用，它们也可能引发胶质细胞分泌炎性细胞因子。为了验证这一假设，我们比较了人胰岛淀粉样多肽和大鼠胰岛淀粉样多肽对U-373 MG人星形细胞瘤细胞中细胞因子产生的影响。单独的人胰岛淀粉样多肽以浓度依赖的方式刺激U-373 MG细胞分泌IL-6和IL-8，在10 - 25 μM肽时可见最大效应。此外，人胰岛淀粉样多肽显著增强IL-1β刺激的细胞因子产生，且具有相似的浓度依赖性。相比之下，非淀粉样变性的大鼠胰岛淀粉样多肽单独或与IL-1β联合使用时，对细胞因子分泌的刺激作用较弱。老化的人胰岛淀粉样多肽导致细胞因子分泌减少，这可能是由于形成了较大且活性较低的聚集体。与我们之前使用Aβ的研究一致，细胞外Ca(2+)对于人胰岛淀粉样多肽刺激细胞因子分泌是必需的。我们的数据表明，具有淀粉样变性的肽通过类似的β-折叠二级结构和细胞外Ca(2+)依赖机制促进细胞因子分泌。
